Enhancing Efficacy of Oncolytic Virotherapy with PDT Preclinical and clinical studies using oncolytic viruses show promise for treating solid tumors. However, systemic delivery of oncolytic viral vectors to tumors is limited by an ineffective entry of the vector to the target site. We propose to explore the potential of oncolytic virotherapy used in combination with photodynamic therapy (PDT) for the treatment of head and neck tumors, for which PDT is an excellent modality. PDT uses activation of tumor localizing photosensitizer (PS) by visible light, and through generation of cytotoxic singlet oxygen induces damage to tumor cells. At Roswell Park Cancer Institute, the PDT group has identified a highly promising PS (HPPH), which is currently in Phase I/II clinical trials. To explore the potential of combination PDT and virotherapy in head and neck squamous cell carcinoma (HNSCC), we propose to investigate the effect of PDT-induced local tumor damage and changes in vascular permeability on the antitumor efficacy of virotherapy treatment in a xenograft model in mice. We found that while a recombinant oncolytic vaccinia virus (rOVV) alone had an impact on reducing tumor volume over time, the combined treatment with the optimally curative PDT regimen improved the antitumor response and tumor-free survival. We hypothesize that optimal PDT treatment conditions resulting in increases in vascular permeability will enhance the uptake and replication of rOVV in tumor tissues leading to ablation of primary tumor and long-term control of disseminated disease. Here, we propose to optimize the rOVV and PDT treatments alone and in combination, and to elucidate the mechanisms of PDT-mediated enhancement of rOVV virotherapy in xenografted HNSCC human tumors. The Specific Aims are: i) We will analyze the extent of histologic structure and vascular differences between SCC xenografts affects rOVV replication in the tumor lesions;ii) Using HPPH and its carbohydrate conjugate (HPPH-Gal), we will investigate the effect of tumor morphology, vascularity and the presence or absence of ABCG2 transporter on efficacy of the PDT treatment;iii) We will explore the kinetics of the rOVV delivery relative to PDT to maximize the benefit of combining the two treatments. PDT results in vascular leakiness and local tumor damage but how the degree of the local tissue response following PDT affects uptake of oncolytic viruses is unknown. These two procedures have different mechanisms of action and there could be an added benefit to combining the two treatments. PERFORMANCE SITE(S) (organization, city, state) Roswell Park Cancer Institute Elm &Carlton Streets Buffalo, NY 14263 PUBLIC HEALTH RELEVANCE: Enhancing Efficacy of Oncolytic Virotherapy with PDT We propose to investigate the effect of photodynamic therapy (PDT)-induced local tumor damage and changes in vascular permeability on the antitumor efficacy of oncolytic virotherapy treatment using xenografts of human head and neck squamous cell carcinomas (HNSCCs) in an immunodeficient mouse model. We hypothesize that optimal PDT treatment conditions resulting in increases in vascular permeability will enhance the uptake and replication of an oncolytic vaccinia virus in tumor tissues leading to ablation of primary tumor and long-term control of disseminated disease.